Interactions between the host innate immune system and the enteric microbiota are proximal events in the pathogenesis of the idiopathic human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depends on using experimental models and human systems to better understand functional interactions between innate immunity and enteric microbes that determine differentiation and activation of effector vs. regulatory T cell subsets in mucosal tissues. We hypothesize that subsets of the commensal microbiota preferentially activate protective vs. destructive innate signaling pathways that integratively activate mucosal innate and antigen presenting cells to secrete cytokines that promote regulatory vs. effector T cell responses. These interacting bacterially- activated innate and adaptive pathways mediate homeostatic vs. effector immune responses and can be manipulated for therapeutic purposes. This hypothesis will be addressed through synergistic efforts of six fully integrated investigators with complementary expertise in innate immunity and host-microbiota interactions, facilitated by two highly utilized cores. Project 1 (Jenny Ting): NOD-like receptors in intestinal inflammation. Project 2 (Balfour Sartor): Role of IL-10 in APC regulation of protective vs. pathogenic T cell responses to commensal bacteria. Project 3 (Scott Plevy): Macrophage IL-10 and IL-12 regulation by the enteric microbiota in intestinal inflammation . Project 4 (John Rawls): Microbial regulation of systemic neutrophil function. The Project Leaders will be supported by two highly interactive cores that have already facilitated collaborative research. Core A: Gnotobiotic and Transgenic Rodent and Zebrafish Core (Core Co- Directors, Drs. Sartor and Rawls). Core B: Human Tissue and Genomics Core (Co-Directors, Drs. Scott Plevy, Hans Herfarth and Shehzad Sheikh). The investigators, facilitated by Cores, are poised to accelerate the understanding of how the innate immune system interacts with the enteric microbiota in health and disease. This knowledge could have a major public health impact upon IBD and the numerous disorders that result from dysregulated innate immune interactions with enteric microbiota.